PROJECT SUMMARY/ABSTRACT Oral mucositis (OM), the inflammation and/or ulceration of the oral mucosa produced by chemotherapy and radiation, is a major complication for patients being treated for squamous cell carcinoma of the head and neck (HNSCC). Known risk factors for OM (e.g., treatment dose, duration, intensity) explain only part of the variation seen in the degree and duration of OM. Further, reports of OM severity vary highly among patients with similar amounts of redness or ulceration. At MD Anderson, patients with head and neck cancer present to the emergency department (ED) with severe OM-related pain (along with dehydration, fatigue, weight loss, nausea, vomiting) as early as 7?10 days from start of treatment for those being treated with chemotherapy and as early as 2?3 weeks for those being treated with radiation. These conditions can lead to reduction in treatment dose, unplanned hospitalizations, breaks in treatment regimen, and reduced quality of life. Subsequent ED visits are common, with OM-related pain persisting as a primary chief complaint across ED visits for 15%?23% of patients. Standard OM treatments?pain control, rehydration, oral hygiene?do not meaningfully influence the OM trajectory. Therefore, there is urgent need for ways to identify patients at high risk for severe OM and to implement novel prevention and intervention strategies in this group. Recent studies suggest that the health of the oral/esophageal mucosal epithelium is directly and consistently affected by its interaction with commensal microflora (the microbiome) and may serve as a predictive biomarker for future health outcomes. Additionally, significant changes in the microbiome during cancer therapy (e.g., a shift to pathogenic species or reduction in oral microbial diversity) suggest that loss of specific commensal flora important for the health of the oral epithelium could be implicated in OM pathophysiology and may serve as an early objective biomarker for the development and severity of OM. Understanding the role of the oral microbiome in the development and severity of OM may inform risk-prediction models and stratification procedures for initiating prompt clinical intervention (thus averting OM-associated ED visits) and could lead to development of targeted therapies for preventing and treating OM. The proposed study will target 2 specific aims: 1) Evaluate the association between baseline microbiome composition and incidence and time to onset of oral mucositis in patients with head and neck cancer; and 2) develop prediction models for incidence and time to onset of oral mucositis. We will include patients with newly diagnosed HNSCC at MD Anderson Cancer Center. We hypothesize that the incidence and severity of OM will vary in relation to changes and differences in the distribution of oral microbial taxa and that oral microbial diversity, in conjunction with clinical, epidemiological, and behavioral data, will be able to identify a subset of patients at high risk for severe OM.